Spinal cord injury (SCI) is a devastating condition that has disabled millions of individuals world-wide. Pathophysiologically, its two principal components are the acute tissue damage directly associated with the inciting injury, and a later phase of delayed injury that occurs over the ensuing days. This latter phase is primarily a consequence of inflammation and inflammatory edema, which reduces parenchymal perfusion, thereby resulting in ischemic extension of the initial injury. Remarkably, this delayed inflammatory injury may lead to more structural damage than the initial injury, and typically accounts for the bulk of neurological morbidity in SCI patients. Most contemporary studies have focused on the late effectors of this inflammatory response;few have sought to identify the upstream initiators of this process. This proposal will thus test the novel postulate that the inflammatory response to traumatic SCI is initiated by astrocytic ATP release, which serves to activate local microglia in a purine receptor-dependent fashion;subsequent inflammatory effectors are released in the setting of this secondary microglial response. The proposal is based on our preliminary observations that traumatic SCI is associated with the pathological release of ATP, and that purinergic receptor antagonists effectively reduced inflammation and improved locomotor recovery after SCI.
Aim 1 will test the postulate that the dysregulated post-traumatic release of ATP is both necessary and sufficient for microglial activation. These experiments will employ novel transgenic mice that have been engineered to release either abnormally high or low levels of astrocytic ATP in response to SCI: ATP release is attenuated in mice lacking astrocytic connexin hemichannels (Cx43/Cx30 KO), but potentiated in mice with an increased number of astrocytic hemichannels (Cx43 G138R mutation).
Aim 2 will attempt to define the pathway intermediates downstream of purinergic activation in the post-traumatic inflammatory response. The effects of genetic and pharmacological manipulations of purinergic signaling on the transcriptional activation of both chemokine and cytokine effectors of SCI will be assessed, so as to define the pathways by which the inflammatory sequelae of purinergic activation are coordinated. Transcriptional changes in microglial gene expression will be analyzed by microarray assessment of FACS-sorted microglia.
Aim 3 will then test the idea that microglial inflammatory mediators trigger astrogliosis and hence astroglial scar formation, which in turn provides the nidus for a sustained increase in local ATP release. As such, this Aim will test the possibility that astrocytic ATP release is increased for weeks to months following SCI. Our hypothesis is that the ATP released from reactive astrocytes may drive the further release of pro-inflammatory mediators, thereby enhancing astrogliosis. Together, these experiments promise to fill critical gaps in our understanding of the role of purinergic signaling in SCI, and should permit us to define purine-regulated genes and gene products critical that might permit the therapeutic suppression of delayed spinal cord injury.

Public Health Relevance

This project will link ATP release and purinergic signaling to microglial cell activation and release of inflammatory agents following spinal cord injury. Our goal is to define targets for development of novel therapeutic to treat acute spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Jakeman, Lyn B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
Schools of Dentistry
United States
Zip Code
Xavier, Anna L; Menezes, João R L; Goldman, Steven A et al. (2014) Fine-tuning the central nervous system: microglial modelling of cells and synapses. Philos Trans R Soc Lond B Biol Sci 369:20130593
Kress, Benjamin T; Iliff, Jeffrey J; Xia, Maosheng et al. (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845-61
Iliff, Jeffrey J; Chen, Michael J; Plog, Benjamin A et al. (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180-93
Takano, Takahiro; He, Wei; Han, Xiaoning et al. (2014) Rapid manifestation of reactive astrogliosis in acute hippocampal brain slices. Glia 62:78-95
Plog, Benjamin A; Moll, Katherine M; Kang, Hongyi et al. (2014) A novel technique for morphometric quantification of subarachnoid hemorrhage-induced microglia activation. J Neurosci Methods 229:44-52
Thrane, Alexander S; Rangroo Thrane, Vinita; Nedergaard, Maiken (2014) Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci 37:620-8
Cotrina, Maria Luisa; Chen, Michael; Han, Xiaoning et al. (2014) Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease. Brain Res 1582:211-9
Tong, Jing; Ren, Yi; Wang, Xiaowei et al. (2014) Assessment of Nogo-66 receptor 1 function in vivo after spinal cord injury. Neurosurgery 75:51-60
Chen, Gang; Park, Chul-Kyu; Xie, Rou-Gang et al. (2014) Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain 137:2193-209
Fields, R Douglas; Araque, Alfonso; Johansen-Berg, Heidi et al. (2014) Glial biology in learning and cognition. Neuroscientist 20:426-31

Showing the most recent 10 out of 26 publications